Innate Immune regulation of helminth-induced inflammation

 描述（由申请方提供）：蠕虫感染，包括旋毛虫，感染全球约20亿人，是一个重大的公共卫生问题。为了对抗这些寄生虫，哺乳动物免疫系统已经进化出在促进减少寄生虫负担所需的有益炎症和限制病理性炎症以维持组织完整性之间维持微妙平衡的机制。维持这种平衡的重要性是显而易见的严重的病理表现在患者表现出失调的免疫反应蠕虫。尽管在蠕虫感染的背景下平衡保护和病理反应的重要性，但调节这些途径的细胞和分子事件仍然未知。已经确定，2型应答是人类和小鼠中蠕虫诱导的免疫应答的特征，需要促进蠕虫清除和限制感染诱导的组织损伤。我们最近的研究表明，特化的蠕虫诱导的造血干/祖细胞（HSPCs）进入外周组织，发育成肥大细胞，并促进TH 2嘌呤依赖性免疫旋毛虫。此外，我们的新的初步数据表明，蠕虫诱导的HSPC上调碳酸酐酶，一个家族的酶，调节pH值和治疗靶向治疗癫痫和青光眼。此外，通过用FDA批准的pan Car抑制剂处理来阻断Car酶活性足以在体外防止鼠和人肥大细胞发育以及在体内防止肥大细胞应答、TH 2细胞因子产生和对旋毛虫的保护性免疫。此外，我们的初步研究表明，汽车依赖性肥大细胞促进单核细胞的反应和肠道替代激活的巨噬细胞群体的存在。这些数据表明Car酶活化的药理学操作可用于在蠕虫感染的情况下调节肥大细胞发育、TH 2细胞因子介导的炎症和伤口愈合反应。基于我们的新数据，两个具体的目标将解决以下问题：（i）可以采用药理学抑制或激活特定的Car酶家族成员来调节旋毛虫诱导的肥大细胞反应和TH 2胆碱介导的炎症？(ii)旋毛虫感染后单核细胞与CAR依赖性肥大细胞协同促进肠道创伤愈合反应吗？总的来说，这些研究将探讨先天免疫机制的新方面，TH 2细胞因子介导的免疫和炎症通过该机制启动。我们预期，确定Car酶调节蠕虫诱导的肥大细胞应答、Th 2细胞因子产生和肠道病理学的机制将显著地为治疗蠕虫感染及其相关发病率的新的免疫治疗策略提供信息。

 DESCRIPTION (provided by applicant): Helminth infections, including Trichinella spiralis, infect approximately 2 billion people worldwide and represent a significant public health concern. To combat these parasites the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation in order to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminthes. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that type 2 responses, characteristic of helminth-induced immune responses in humans and mice, are required to both promote worm clearance and limit infection- induced tissue damage. Our recent studies have demonstrated that specialized helminth-induced hematopoietic stem/progenitor cells (HSPCs) enter peripheral tissues, develop into mast cells and promote TH2 cytokine-dependent immunity to Trichinella spiralis. In addition, our novel preliminary data reveal that helminth-induced HSPCs upregulate Carbonic anhydrase enzymes, a family of enzymes that regulate pH and are targeted therapeutically to treat epilepsy and glaucoma. Further, blocking Car enzyme activity via treatment with FDA approved pan Car inhibitors was sufficient to prevent murine and human mast cell development in vitro and mast cell responses, TH2 cytokine production and protective immunity to Trichinella in vivo. Moreover, our preliminary studies indicate that Car-dependent mast cells promote monocyte responses and the presence of intestinal alternatively activated macrophage populations. These data indicate that pharmacologic manipulation of Car enzyme activation could be employed to regulate mast cell development, TH2 cytokine- mediated inflammation and wound healing responses in the context of helminth infections. Based on our new data, two specific aims will address the following questions: (i) Can pharmacologic inhibition or activation of specific Car enzyme family members be employed to regulate Trichinella-induced mast cell responses and TH2 cytokine-mediated inflammation? (ii) Do monocytes cooperate with Car-dependent mast cells to promote intestinal wound healing responses following Trichinella infection? Collectively, these studies will interrogate novel aspects of innate immune mechanisms through which TH2 cytokine-mediated immunity and inflammation are initiated. We anticipate that defining the mechanisms through which Car enzymes regulate helminth- induced mast cell responses, Th2 cytokine production and intestinal pathology will significantly inform new immune therapeutic strategies to treat helminth infections and their associated morbidities.